CN1230188A - 25-methylene and 24,25-epoxy marcfortines and paraheroquamides - Google Patents
25-methylene and 24,25-epoxy marcfortines and paraheroquamides Download PDFInfo
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- CN1230188A CN1230188A CN97197774A CN97197774A CN1230188A CN 1230188 A CN1230188 A CN 1230188A CN 97197774 A CN97197774 A CN 97197774A CN 97197774 A CN97197774 A CN 97197774A CN 1230188 A CN1230188 A CN 1230188A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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Abstract
The present invention are marcfortines and paraherquamides where the 7-member oxygenated ring has been modified to produce 25-methylene compounds (VII) and 24,25-epoxy compounds (VIII) all of which are useful as antiparasitic agents against endo and ecto parasites, particularly helminths and arthropods.
Description
The present invention relates to be suitable for (replacement) 25-methylene radical and 24,25-epoxy marcfortine (marcfortines) and the paraheroquamide (paraherquamides) of making antiparasitic.
Marcfortine is a known compound, see " Chemical Society's chemical communication magazine " (Journal of theChemical Society Chemical Communications), 601-602 (1980) is about marcfortine A and " tetrahedron communication " (Tetrahedron Letters), 22,1977-1980 (1981) is about marcfortine B and C.These compounds are meta-bolitess of fungi penicillum requeforti (Penicilliumroqueforti).Marcfortine is structurally relevant with the paraheroquamide that also is known compound.
Paraheroquamide is disclosed " tetrahedron communication ", and 22,135-136 (1981), and " microbiotic magazine " (Journal ofAntibiotics), 44, among the 492-497 (1991).United States Patent (USP) 4,866,060 and 4,923,867 disclose marcfortine A, B and C and some derivative thereof the application aspect treatment and prevention animal parasitosis.
WO92/22555 (on December 23rd, 1992 is disclosed) has described a kind of marcfortine or paraheroquamide derivative (i.e. the formula III of the part that replaces with methyl or methyl and hydroxyl) prevailingly on position 14, but describes how to prepare this 14-methyl isophthalic acid 4-hydroxyl marcfortine compound.
" microbiotic magazine ", 43,1380-1386 (1990) discloses the paraheroquamide A with following structure:
Marcfortine A has following structure:
Marcfortine B has following structure:
Marcfortine C has following structure:
Marcfortine D has following structure:
WO91/09961 (on July 11st, 1991 is disclosed) discloses the various derivatives of marcfortine and paraheroquamide, and 12a-N-oxide compound, and the production method of especially producing VM29919 (paraheroquamide) and VM55596 (the 12a-N-oxide compound of paraheroquamide) from Penicillium bacterial classification (PenicilliumSp.) IMI332995.
United States Patent (USP) 4,873,247 disclose the derivative of paraheroquamide and bacterial strain charles mould (Penicillium charlessi) MF5123 (ATCC 20841) of production paraheroquamide.The method that United States Patent (USP) 4,978,656 (and EP390532-A, EP-301742-A) disclose various synthetic paraheroquamide derivatives and produced paraheroquamide from charles's mould MF5123 (ATCC 20841).
International open WO92/22555 (on December 23rd, 1992 is disclosed) discloses 14 Alpha-hydroxy marcfortine compounds prevailingly and has used the method that 14-hydroxyl-14-methyl marcfortine compound is produced anti-parasite medicine.But, any method for preparing 14 Alpha-hydroxy marcfortines or 14 Alpha-hydroxies-14 Beta-methyl marcfortine compound is described.
International open WO94/29319 discloses marcfortine and the derivative thereof that various 14-replace.
15-alkyl-14-oxy-compound (III) (n wherein
1Be 0) be known compound, see international open WO94/29319.
The invention discloses the 25-methylene compound of formula (VII), wherein about:
(I) marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-H, and R
14 βBe-H,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H;
(II) paraheroquamide A
(a) n is 0,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe-CH
3,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H; (III) 14-hydroxyl-14-alkyl marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe C
1-C
4Alkyl,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H; (IV) 14-hydroxyl-15-methyl marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe-H,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe C
1-C
4Alkyl, and R
15 βBe-H and pharmaceutically acceptable salt thereof.Also disclose formula (VIII) 24, the 25-epoxy compounds is wherein about (I) marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-H, and R
14 βBe-H,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H; (II) paraheroquamide A
(a) n is 0,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe-CH
3,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H; (III) 14-hydroxyl-14-alkyl marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe C
1-C
4Alkyl,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H; (IV) 14-hydroxyl-15-methyl marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe-H,
(c) R
15Be R
15 α: R
15 β, wherein R15 α is C
1-C
4Alkyl, and R
15 βBe-H and pharmaceutically acceptable salt thereof.
N-(18a)-demethylation-2-deoxidation paraheroquamide A and pharmaceutically acceptable salt thereof is disclosed.
The present invention relates to 25-methylene radical (VII) and 24,25-epoxy (VIII) marcfortine and paraheroquamide.These compounds prepare by two kinds of differential responses from known compound.
25-methylene radical marcfortine and paraheroquamide (VII) prepare from known corresponding cyclenes (I).When (a) n is 1, (b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-H, and R
14 βBe-H and (c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-during H, then initial cyclenes (I) is marcfortine A; When (a) n is 0, (b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe-CH
3And (c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and 15 β be-during H, then initial cyclenes (I) is paraheroquamide A; When (a) n is 1, (b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe-CH
3And (c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-during H, then initial cyclenes (I) is 14-hydroxyl-14-methyl marcfortine A; When (a) n is 1, (b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe-H and (c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-CH
3, and R
15 βBe-during H, then initial cyclenes (I) is 14-hydroxyl-15-methyl marcfortine A.Marcfortine A and paraheroquamide A are well-known compound.Compound 14-hydroxyl-14-alkyl marcfortine A and 14-hydroxyl-15-alkyl marcfortine A prepares by the method that provides among Table A and B and the preparation example 1-31." table " and " preparation example " exemplified by methyl is as alkyl substituent, but those skilled in the art will know that and can prepare ethyl, propyl group and butyl (also comprising its isomer if present) in a similar manner.
25-methylene compound (VII) is to prepare from corresponding cyclenes (I) like this: at first use reagent (as formic acid) the seven-membered ring ether-splitting that contains this alkene is separated production glycol (II).Make (II) alkylation of this glycol and generate corresponding alkene (III) with alkylating agent again.Alkene (III) must have two keys to prepare required product in certain location, and promptly after cyclisation and oxidation, this product will have a hydroxyl on C-25.This reagent comprises formula X
1-CH
2-CH=C (CH
3)
2Compound, X wherein
1Be leavings group, as-Br or-Cl; Preferred X
1Be-Br that more preferably this reagent is 4-bromo-2-methyl-2-butene.In the presence of potassiumiodide and weak base such as supercarbonate or carbonate (preferably salt of wormwood), in water-ORGANIC SOLVENT MIXTURES (preferably acetone), carry out this reaction.Use peracid (between preferably using-chlorine peroxybenzoic acid) then this alkene (III) is oxidized to corresponding epoxy phenol (IV), then handle with sodium bisulfite.Use tin chloride (IV) again this epoxy phenol (IV) is cyclized into corresponding cyclic alcohol (V).Down this cyclic alcohol (V) is oxidized to corresponding ketone (VI) in Swern condition (oxalyl chloride, DMSO then handle with TEA) then.By Wittig reactive applications first base three phenyl phosphonium bromides and highly basic (as n-Butyl Lithium) this ketone (VI) is transformed into required 25-methylene compound (VII) again.Recognize that this 25-methylene compound (VII) is 24, the 25-dihydro-compound.
24,25-epoxy compounds (VIII) is such preparation: be oxidizing to the corresponding cyclenes of oxidation (I) under the normal condition of epoxide with peracid at peracid, then handle with aqueous solution of sodium bisulfite.Preferred this peracid be between-the chlorine peroxybenzoic acid.
N-(18a)-demethylation-2-deoxidation paraheroquamide A is also referred to as (1 ' α, 5 ' α β, 7 ' β, 8 ＇ α β, 9 '+β)-(-)-2,2 ', 3,3 ', 8a ', 9 '-six hydrogen-1 '-hydroxyl-1 ', 4,4,8 ', 8 '-pentamethyl--spiral shell [4H, 8H,-[1,4] dioxy (dioxepino) [2,3-g] indoles-8,7 ' (8 ' H)-[5H, 6H-5a, 9a] (imino-methylene radical) [1H] encircles penta [f] indolizine]-9-ketone].N-(18a)-demethylation-2-deoxidation paraheroquamide A can see embodiment 14 and 15 by two kinds of different methods preparations.
25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A is an amine, so form acid-adducting salt when the acid-respons of they and sufficient intensity.Pharmaceutically acceptable salt comprises mineral acid and organic acid salt.Pharmaceutically acceptable salt than corresponding unhindered amina more preferably because the compound water soluble that their produce is bigger, easier crystallization.Preferred pharmaceutically acceptable salt comprises the salt of following acid, i.e. methylsulfonic acid, hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, phenylformic acid, citric acid, tartrate, fumaric acid, toxilic acid, CH
3-(CH
2)
n-COOH (wherein n is 0～4), HOOC-(CH
2)
n-COOH (wherein n is with above-mentioned definition).
Be surprised to find that 25-methylene compound of the present invention (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A is anti-endoparasite and epizoon, especially anthelmintic and arthropodan effective antiparasitic, described parasite cause the multiple parasitosis of people, animal and plant.
Parasitosis can cause by endoparasite or epizoon.Endoparasite is this parasite, i.e. their existence is in host, perhaps in organ (as stomach, lung, heart, intestines etc.) or just subcutaneous.Epizoon is that existence is at host's outside surface but still absorb the parasite of nutritive substance from the host.
The endoparasite disease is commonly referred to as verminosis, is owing to the parasitic infection host who is called as worm causes.Verminosis is the serious worldwide economic problems that prevail, and it is because the infection of domesticate animals (as pig, sheep, horse, ox, goat, dog, cat and poultry) causes.It much is that worm by being called as nematode causes that this nematode causes the disease of multiple animal in the world that these infection have.This class disease is very serious usually, can cause infected animals death.The most common Turbatrix that infects above-mentioned animal is Haemonchus (Haemonchus), trichostrongylus (Trichostrongylus), Ostertagia (Ostertagia), Nematodirus (Nematodirus), Cooperia (Cooperia), roundworm (Ascaris), Bunostomum (Bunostomum), oesophagostomum (Oesophagostomum), Chabertia (Chabertia), Trichocephalus (Trichuris), strongylid (Strongylus), trichinella (Trichonema), Dictyocaulus (Dictyocaulus), Hepaticola (Capillaria), Heterakis (Heterakis), Belascaris (Toxocara), Ascaridia (Ascaridia), Oxyuris (Oxyuris), Ancylostoma (Ancylostoma), Ancylostoma (Uncinaria), Toxascaris (Toxascaris), and parascris (Parascaris).A lot of parasite are species specificity (only infecting a kind of host), and great majority also have preferred infection site in animal.So Haemonchus and Ostertagia mainly infect stomach, Nematodirus and Cooperia are then attacked intestines usually.Some likes other parasite colonizing in the heart, eye, lung, the blood vessel etc., and other then are subcutaneous parasite.Verminosis can cause weakness, loss of weight, anaemia, damage of intestines, malnutrition and to the damage of other organ.Will not cause animal dead if do not cure these diseases.
The infection of ectoparasite arthropods (as tick (ticks), mite (mites), lice (lice), tatukira (stableflies), horn fly (hornflies), calliphorid (blowflies), flea (fleas) etc.) also is serious problem.These parasitic infection cause losing blood, skin injury, and can disturb normal food habits and cause loss of weight.These infection also can cause propagating serious disease (as encephalitis, anaplasmosis, swine pox etc.), and this class disease can be fatefulue.
Animal may be subjected to several parsitism simultaneously, because a kind of parasite can make animal become weak, so make it more be subject to second kind of parsitism.So it is useful especially in this class treatment of diseases to have the compound of broad spectrum of activity.This 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A unexpectedly has anti-these parasitic high reactivities, in addition, also has anti-following parasitic activity, it is the Dirofilaria (Dirofilaria) in the dog, Nematospiroides in the rodent and Syphacia (Syphacia), biting insects in the ox and migrate Diptera larvae (as the kind (Hypoderma sp.) of Hypoderma), and the Gasterophilus of Malaysia and China (Gastrophilus).
This 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A also are fit to anti-endoparasite and the epizoon that causes people's parasitosis.The endoparasite example of this class infected person comprises the stomach and intestine parasite of dependent of dead military hero down: Ancylostoma, Necator (Necator), roundworm, Strongyloides (Strongyloides), Trichinella (Trichinella), Hepaticola, Trichocephalus, Enterobius (Enterobius) etc.Other endoparasite of infected person sees in blood or other organ.The parasitic example of this class has filaria Wuchereria (Wucheria), Brugia (Brugia), Onchocerca (Onchocerca) etc., and the outer phase of the intestines of intestines worm strongylid (Strongylides) and Trichinella.The epizoon that parasitizes the people comprises arthropods, and as tick, flea, mite, lice etc., and for domesticate animals, these parasitic infection can cause propagating serious disease and even fatal diseases.This 25-methylene compound (VII), 24, all anti-effectively these endoparasites of 25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A and epizoon, anti-effectively in addition biting insects and other Diptera pest of bothering the people.This 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-dose rate of 2-deoxidation paraheroquamide A when being used by oral or non-enteron aisle is 0.05～20mg/Kg the weight of animals.
This 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A also is applicable to anti-house pest, belongs to (Blatella sp.) (cockroach), casemaking clothes moth as Lian and belongs to that (Tineola sp.) (casemaking clothes moth), hair are moth-eaten to belong to (Attagenus sp.) (khapra beetle), housefly (Musca domestica) and the counter infrared ray ant (Solenopsis invicta) (imported fire ant) of flaring up.
This 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A also is applicable to anti-Agricultural pests, for example aphid (no net long tube Aphis (Acyrthiosiphon sp.)), locust and boll weevil, and the insect pest of anti-invasion storage cereal, for example Tribolium (Tribolium sp.) also resists the insect that lives in mezzanine level in the plant tissue.This 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A also are suitable for and do control may be the nematocides that agricultural goes up important soil nematodes.
During as the antiparasitic in the animal, this 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A can be by per os or by using in the injecting body, perhaps as the liquid perfusion or as shampoo and topical application.
As for oral, the form that this 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A can be capsule, tablet or gavage big ball is used, and perhaps can mix with animal-feed and use.This capsule, tablet and gavage big ball and comprise activeconstituents are in conjunction with suitable carrier, as starch, talcum, Magnesium Stearate or Lin Suanergai.These unit dosage forms are preparations like this, promptly by activeconstituents is closely mixed with suitable finely powdered inert component (comprising thinner, filler, disintegrating agent, suspension agent and/or tackiness agent), so get homogeneous mixture solotion or suspension.Inert component is such material, promptly not with this 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A reaction, and nontoxic to subject animal.Suitable inert component comprises starch, lactose, talcum, Magnesium Stearate, vegetable jelly and wet goods.These preparations can contain the active ingredient and the inactive ingredients of very wide variable quantity, and this depends on multiple factor, for example size of animal to be treated and classification, the classification of infection and seriousness.Active ingredient also can be used as fodder additives and uses, only need simply with this 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A mixes with feed or this compound is executed the feed surface.Also active ingredient can be mixed with inert support, again resulting composition be mixed with feed or direct feeding to animal.Suitable inert support comprises Semen Maydis powder, citrus pulp, fermentation residue, soybean residue, dried grains etc.With active ingredient and these inert supports by pulverize, stirring, abrasive dust or lift-over and closely mix, make final composition contain 0.001～5.0wt% active ingredient.
25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A also can be used by non-enteron aisle, i.e. the preparation that is made of the active ingredient that is dissolved in inert liquid carrier by injection.Can pass through in the intramuscular, tube chamber, in the tracheae or subcutaneous injection.The injectivity preparation is mixed by active ingredient and suitable inert liquid carrier.Acceptable liquid vehicle comprises vegetables oil, as peanut oil, oleum gossypii seminis, sesame oil etc., and organic solvent, as colloidal sol ketal, Sericosol N etc.Also can use aqueous parenteral formulation.Vegetables oil is preferred liquid vehicle.Said preparation makes final composition contain 0.005～20wt% active ingredient by active ingredient being dissolved in or being suspended in the liquid vehicle preparation.
But this 25-methylene compound (VII), 24 of topical application, 25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A, promptly by application be the aqueous solution or suspension, contain this 25-methylene compound (VI), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A gavages liquid or shampoo.Common suspending agent-containing of these preparations such as bentonite, and generally also comprise defoamer.The preparation that contains 0.005～20wt% active ingredient is acceptable.Preferred preparation contains 0.5～5wt%25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A.
This 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A mainly are suitable for the verminosis that is used for the treatment of and/or prevents domesticate animals (as ox, sheep, horse, dog, cat, goat, pig and poultry) as antiparasitic.They also are applicable to prevention and treat these animals by the parsitism of epizoon (as tick, mite, lice, flea etc.).They also can effectively treat people's parsitism.When treating such infection, this 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A can be used separately or mutual combination is used or make up usefulness with other incoherent antiparasitic.Reach this required 25-methylene compound (VII), 24 of best effect, the dosage of 25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A depends on several factors, for example classification of animal and size, the classification and the seriousness that infect, the concrete 25-methylene compound (VII), 24 of the methods and applications of using, 25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A.With mode oral this 25-methylene compound (VII), 24 under the dosage of 0.005～50mg/kg the weight of animals of single dose or space-number sky several dosage, 25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A provides good result usually.This 25-methylene compound (VII), 24, the single dose of one of 25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A provides the good control effect usually, infects or anti-unusual persistent parasite with anti-but can provide repeated doses again.Use this 25-methylene compound (VII), 24 to animal, the method for 25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A is known to the skilled in the veterinary applications.
This 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A also can be used for the Agricultural pests of the crop anti-invasion field or storage.In this class was used, with this 25-methylene compound (VII), 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A was used as the crop that spraying fluid, pulvis, emulsion etc. are used for growing plants or have gathered in the crops.Use 25-methylene compound (VII), 24 in this mode, the method for 25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A is known to the skilled in the agriculture field.
Accurate dosage of using and number of times depend on the concrete 25-methylene compound (VII) of application, 24,25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A, the subject concrete patient's condition, treated the seriousness of the patient's condition, concrete patient's age, body weight, comprehensive physical appearance, other pharmacotherapy that can take individuality is well known to those skilled in the art, and can be by measuring this 25-methylene compound (VII) in blood flow volume or the blood samples of patients, 24, the concentration of 25-epoxy compounds (VIII) and N-(18a)-demethylation-2-deoxidation paraheroquamide A and/patient measures more accurately to the response of being treated the concrete patient's condition.
Following definition and explanation are the terms at the whole text application that comprises specification sheets and claim.
I. to the regulation of formula with to the definition of variable
The chemical formula of each compound or molecule fragment also can comprise variable substituents in expression specification sheets and claims except the constitutional features of expressing regulation.These variable substituents are by the letter difference of letter or band numeric suffix, for example " Z
1" or " R
i", wherein " i " is integer.These variable substituting groups can be unit price or divalence, i.e. the group that their expressions are connected with formula by one or two chemical bond.For example, group Z
1If with formula CH
3-C (=Z
1-) H connects and just to represent the variable base of divalence.Radicals R
iAnd R
iIf with formula CH
3-CH
2-C (R
i) (R
i)-H connects and just represents the variable substituting group of monovalence.If chemical formula draws with line style, as above-mentioned formula, the variable substituting group that is contained in the bracket directly is connected on the atom that is included in the variable substituting group immediate left in the bracket.When the variable substituting group of two or more successive is included in the bracket, in the continuous variable substituting group each all be not included in bracket in the previous atom of immediate left be connected.So, in following formula, R
iAnd R
iAll be connected with previous carbon atom.Also have, for any molecule that definite carbon atoms numbered system is arranged, steroide for example, these carbon atoms are marked as C
i, wherein " i " is the integer corresponding to carbon atom number.C for example
6Represent the carbon atom number in the technician is accustomed to stipulating in No. 6 positions or the steroid chemistry field the steroid nucleus.Equally, term " R
6" expression C
6Locational variable substituting group (unit price or divalence).
The chemical formula that draws with line style or its part are represented the atom in the linear chain.Two interatomic keys in symbol "-" the ordinary representation chain.So CH
3-O-CH
2-CH (R
i)-CH
3Expression 2-replaces-1-methoxy propyl hydride compounds.With the same manner, symbol "=" expression two key, for example CH
2=C (Ri)-O-CH
3, symbol " ≡ " is then represented three key, as HC ≡ C-CH (R
i)-CH
2-CH
3Carbonyl with any expression of following dual mode :-CO-or-C (=O)-, preceding a kind of because of simple by preferred.
The chemical formula of ring compound or molecule fragment can line style be represented.Like this, compound 4-chloro-2-picoline can line style N
*=C (CH
3)-CH=CCl-CH=C
*H represents, indicate as usual asterisk (
*) atom mutually combine and form ring.Equally, ring molecule fragment 4-(ethyl)-1-piperazinyl can-N
*-(CH
2)
2-N (C
2H
5)-CH
2-C
*H
2Expression.
The rigid annular structure of this paper any compound has been stipulated substituting group that each carbon atom of this rigid annular compound the connects orientation about plane of a loop.As for the saturated compound on the carbon atom that has two substituting groups to be connected in to belong to the ring system part ,-C (X
1) (X
2)-two substituting group can be upright or equatorial position with respect to ring, and can uprightly/calm between conversion.But, two substituting groups are maintained fixed with respect to ring and mutual position.Though arbitrary substituting group may be arranged in plane of a loop (calm) sometimes rather than above or below planar (uprightly), a substituting group is always above another.In describing the chemical structural formula of this compound, be positioned at another substituting group (X
2) substituting group (X of " below "
1) be defined as the α configuration, be connected on the carbon atom by dotted line, deshed line or long and short dash line, promptly by symbol "---" or " ... " expression.Be connected another substituting group (X
1) the corresponding substituting group (X of " top "
2) be defined as beta comfiguration, represent by the solid line that is connected on this carbon atom.
When variable substituting group was divalence, valence link can be together or this variable bases of definition independently or all with having.For example, be connected in variable basic R on the carbon atom
iAs-C (=R
i)-may be divalence, and may be defined as oxo or ketone group and (so form carbonyl (CO-)), or be defined as the variable substituents alpha-R of monovalence of two separate connection
I-jAnd β-R
I-kAs the variable basic R of divalence
iWhen being defined as comprising the variable substituting group of two monovalencies, the conventionally form that is used to define the variable base of this divalence is " α-R
I-j: β-R
I-k" or its certain variant.In this case, α-R
I-jAnd β-R
I-kAll be connected in formation-C (α-R on this carbon atom
I-j) (β-R
I-k)-.For example, as the variable basic R of divalence
6,-C (=R
6When)-be defined as comprised the variable substituting group of two monovalencies, these two variable substituting groups of monovalence were α-R
6-1: β-R
6-2... α-R
6-9: β-R
6-10Deng, provide-C (α-R
6-1) (β-R
6-2)-...-C (α-R
6-9) (β-R
6-10)-etc.Equally, as for the variable basic R of divalence
11,-C (=R
11Two variable substituting groups of monovalence of)-, are α-R
11-1: β-R
11-2As for there not being the independently annular substituting group of α and β orientation (for example owing to have carbon-carbon double bond on the ring), and, must use afore mentioned rules, but save α and β defines as for the substituting group that is connected on the carbon atom that does not belong to loop section.
May be defined as two independently the variable substituting group of monovalence as the variable base of divalence, two independently the variable substituting group of monovalence also may be defined as and form the variable base of divalence together.For example, at formula-C
1(R
i) H-C
2(R
i) H-(random separate provision C
1And C
2Be first and second carbon atom) in, R
iAnd R
jCan be defined as and form (1) C together
1And C
2Between second key or (2) divalent radicals such as oxa-(O-), so this formula is described epoxide.Work as R
iAnd R
jWhen forming more complicated integral body such as group-X-Y-together, orientation that then should integral body should make the C in the following formula
1Be connected on the X, and C
2Be connected on the Y.So, in accordance with regulations " ... R
iAnd R
jFormation-CH together
2-CH
2-O-CO-... " the expression lactone, wherein carbonyl is connected in C
2On.But, when the definition " ... R
jAnd R
iFormation-CO-O-CH together
2-CH
2-" time, then represent lactone traditionally, wherein carbonyl is connected in C
1On.
Variable substituent carbon content is represented with one of following two kinds of methods.First method is used the prefix of variable basic full name, for example " C
1-C
4", wherein " 1 " and " 4 " is the integer of expression minimum and maximum carbonatomss in the variable base.With at interval prefix and variable base being separated.For example, " C
1-C
4Alkyl " alkyl of 1～4 carbon atom of expression, (unless provide in contrast representation, otherwise also comprise its isomeric form).Whenever providing this single prefix, the whole carbon contents of variable base that define represented in this prefix.So " C
2-C
4Alkoxy carbonyl " group CH described
3-(CH
2)
n-O-CO-, wherein n is 0,1 or 2.Second method is, only points out the carbon content of each definitional part separately, promptly with bracket with " C
i-C
j" this definition bracket and it be right after (continuously every) under the definitional part front.By this optional convention, " (C
1-C
3) alkoxy carbonyl " and " C
2-C
4Alkoxy carbonyl " same meaning, because " C
1-C
3" only refer to the carbon content of alkoxyl group.Similarly, though " C
2-C
6Alkoxyalkyl " and " (C
1-C
3) alkoxyl group (C
1-C
3) alkyl " all define the alkoxyalkyl that contains 2～6 carbon atoms; but these two definition are different; because previous definition can make alkoxyl group or moieties contain 4 or 5 carbon atoms separately, but a back definition all is limited in 3 carbon atoms with each of this two groups.
When in right requires, containing quite complicated (ring-type) substituting group, then will provide note with bracket after this concrete substituent word of name/definition, this note is corresponding to the same names/definition one of among the figure that this concrete substituent chemical structural formula also will be shown.
II-definition
All temperature are all with a degree centigrade expression.
THF refers to tetrahydrofuran (THF).
DMSO refers to methyl-sulphoxide.
LDA refers to the di-isopropyl lithamide.
TEA refers to triethylamine.
DMF refers to dimethyl formamide.
Salt solution refers to saturated sodium-chloride water solution.
Chromatogram (column chromatography and hurried chromatogram) refers to the purifying of the compound of expressing with (carrier, eluent)/separate.Should understand suitable fraction to be compiled and concentrate and to get required compound.
NMR refers to nuclear (proton) magnetic resonance spectrum, with low ppm (δ) the report chemical shift of tetramethylsilane.
-φ refers to phenyl (C
6H
5).
MS refers to mass spectrum, expresses with m/e, m/z or mass unit.[M+H]
+Refer to that parent adds the positive ion of hydrogen atom.EI refers to electron-bombardment.CI refers to chemi-ionization.FAB refers to fast atom bombardment.
HRMS refers to high resolution mass spec.
Ether refers to ether.
" pharmaceutically acceptable " refers to consider acceptable performance of patient and/or material from pharmacology/toxicology angle, refers to that also the pharmacy pharmacist considers that from the physical/chemical angle about composition, preparation, stability, patient's acceptability and biological availability be acceptable.
When solvent-applied to the time, the solvent ratio of application is that volume/volume is than (v/v).
When the solubleness of applying solid in solvent, solid is weight/volume (wt/v) with the ratio of solvent.
"-" expression connects base 2 kinds of possible orientations: α or β when (1) is connected with the steroid ring, and (2) cis when being connected with double-linked carbon or trans.
UC#### refers to Upjohn cultivation abcd.
Embodiment
Need not further elaborate, believe that those skilled in the art can the application of aforementioned explanation farthest implement the present invention.Following detailed embodiment has described and how to prepare all cpds of the present invention and/or implement the whole bag of tricks of the present invention, and it is illustrative these embodiment should being regarded as, is not by any way to the restriction of aforementioned open explanation in any case.Those skilled in the art will recognize at once about reactant and about the suitable change form of reaction conditions and technology.Preparation example 1 16-iodo-17-cyano group marcfortine A non-enantiomer mixture (formula 5)
(11-7g, (this reaction mixture of heating is consumed (about 5hr) until whole marcfortine A under refluxing for 10-5g, the 22mmol) solution in cyanoform (150mL) 76-5mmol) to add marcfortine A with the solid cyanogen iodide.Cooling gained mixture to 20～25 ℃ with methylene dichloride (100mL) dilution, with the saturated sodium bicarbonate solution washing, washs with sodium sulfite solution again.Separate organic phase, after drying on the sal epsom, be concentrated into dried.With chromatography (silica gel; Ethyl acetate/hexane, 3/2) handle the thick solids of gained and title compound.Preparation example 2 16,17-dehydrogenation-17-cyano group marcfortine A (formula 6)
With 16-iodo-17-cyano group marcfortine A (preparation example 1,9.5g 15mmol) are dissolved in methyl alcohol (150mL), add potassium hydroxide aqueous solution (45%, 3mL).Stir this reaction mixture down at 20～25 ℃ and reach 2hr.Add water, filter and collect the precipitation that forms, wash with water, drying under reduced pressure spend the night title compound.Preparation example 3 17-ketone group marcfortine A (formula 7)
(2.9g 26mmol) adds 16, and (preparation example 2,6.0g 10mmol) in the solution of 95% ethanol (100mL), stir this reaction mixture down at 20～25 ℃ and reach 2hr in 17-dehydrogenation-17-cyano group marcfortine A with tin anhydride.Add saturated sodium bicarbonate (100mL) and make the reaction all standing.(2 * 200mL) extract the gained mixture with methylene dichloride.United extraction liquid, dry (sal epsom), concentrate crude product.With chromatography (silica gel; Ethyl acetate) this material of purifying gets title compound, and ([M+H] is about C for FAB, M/Z for HRMS
28H
33N
3O
5The calculated value of+H=492.2498, measured value=492.2478.
Select ground fully, and more preferably, can use right-toluenesulphonic acids synthesising title compound.Like this, right-toluenesulphonic acids monohydrate (1g) is added 16,17-dehydrogenation-17-cyano group marcfortine A (10g) stirs 1hr with this reaction mixture under 20～25 ℃ in the solution of 95% methyl alcohol (50mL).In this mixture, add triethylamine (2mL), the revaporization solvent.With resistates and aqueous sodium carbonate (10%, 100ml) grind, filter out solid, dry solid-state title compound (90% productive rate).Preparation example 4 15,16-dehydrogenation-17-ketone group marcfortine A (formula 8)
From the solution of n-Butyl Lithium in hexane (1.6M, 9.9mL, 15.4mmol) and Diisopropylamine (2.2mL, 15.7mmol) solution of preparation di-isopropyl lithamide.(THF, 20mL) dilution is cooled to-78 ℃ again with anhydrous tetrahydro furan.(4.1mmol) solution in anhydrous THF (20mL) makes reaction mixture be warmed to-40 ℃ during 1hr for preparation example 3,2.0g to drip 17-ketone group marcfortine A.This mixture is cooled to-78 ℃ again, (19mg, THF 5.2mmol) (10mL) solution drip and handle to use the phenyl Selenium monochloride again.Make the reaction all standing with saturated sodium bicarbonate solution after 5 minutes, use dichloromethane extraction, dry (sal epsom), concentrate solids, be not further purified its direct application.This material is dissolved in THF (150mL), and usefulness hydrogen peroxide under 0 ℃ (30%, 1.5mL) handle.Remove cooling bath, stir this reaction mixture down at 20～25 ℃ and reach 30 minutes.(1N 100mL) makes the reaction all standing to add sodium hydroxide.(2 * 200mL) extract this mixture with methylene dichloride.United extraction liquid, dry (sal epsom) back concentrate crude product.With chromatography (silica gel; Ethyl acetate) purifying gets title compound, and ([M+H] is about C for FAB, M/Z for HRMS
28H
31N
3O
5The calculated value of+H=490.2342, measured value=490.2345.Preparation example 5 14 Alpha-hydroxies-15, oxa-aziridine (Oxaziridine) chemistry is used in 16-dehydrogenation-17-ketone group marcfortine A (formula 9a)
(0.5M, 1mL 0.5mmol) are added drop-wise to 15, and (preparation example 4,66mg is in THF 0.14mmol) (2mL) solution in 16-dehydrogenation-17-ketone group marcfortine A with the solution of two (trimethyl silyl) ammonification potassium in toluene under-78 ℃.During 1hr, make the gained mixture be warmed to-40 ℃.This reaction mixture is cooled to-78 ℃, stirred 15 minutes, sulphonyl-3-phenyl oxa-aziridine (42mg, handle by THF 0.16mmol) (2mL) solution by dripping the 2-phenyl then.This mixture was stirred 5 minutes, add sodium bicarbonate then and make the reaction all standing.(2 * 25mL) extract this mixture with methylene dichloride.United extraction thing, dry (sal epsom) back concentrate thick material.By preparative thin layer chromatography (silica gel; Ethyl acetate) purifying gets title compound, and HRMS (FAB, M/Z[M+H]) about C
28H
31N
3O
6The calculated value of+H=506.2291, measured value=506.2280.
Must 14,15-dehydrogenation-16-hydroxyl-17-ketone group marcfortine A (14mg, 20%).Preparation example 6 14 Alpha-hydroxies-15,16-dehydrogenation-17-ketone group marcfortine A
(formula 9a), 15,16-dehydrogenation-14,17-diketo marcfortine A
(formula 11) and 14,15-dehydrogenation-16,17-diketo marcfortine A
(formula 24) uses tin anhydride
With 15, (preparation example 4,1.29g 2.6mmol) are dissolved in-dioxs (30mL), handle with tin anhydride (390mg) in 16-dehydrogenation-17-ketone group marcfortine A.With this mixture backflow 1hr, steaming under reduced pressure desolventizes.Resistates and methylene dichloride (30mL) are ground, refilter.Concentrated filtrate is with chromatography (silica gel; Methanol/ethyl acetate, 1/20) handle resistates and 14 Alpha-hydroxies-15,16-dehydrogenation-17-ketone group marcfortine A (430mg, 32%) solids.Also get 15,16-dehydrogenation-14,17-diketo marcfortine A (formula 11,212mg, 16%) and 14,15-dehydrogenation-16,17-diketo marcfortine A (formula 24,106mg, 8%) from chromatography.Preparation example 7 15,16-dehydrogenation-14,17-diketo marcfortine A (preparation example 11)
With 14 Alpha-hydroxies-15,16-dehydrogenation-17-ketone group marcfortine A (preparation example 6,60mg, formula 9a) is dissolved in methylene dichloride (10mL), handles with Manganse Dioxide (60mg).After under 20～25 ℃ this mixture being stirred 1hr, concentrate.With preparative thin layer chromatography (silica gel; Dichloromethane/ethyl acetate, 50/50) the purifying resistates gets title compound.Preparation example 8 14 Alpha-hydroxy marcfortine A (formula 10)
With 14 Alpha-hydroxies-15, (preparation example 6,20mg 0.040mmol) are dissolved in THF (5mL), use lithium aluminum hydride (1M, 0.11mL, THF solution-treated 0.11mmol) down at 0 ° in 16-dehydrogenation-17-ketone group marcfortine A.Stir this mixture down at 0 ° and reach 0.5hr, add the solution (10%) of sodium bicarbonate then.(2 * 10mL) extract this mixture with methylene dichloride.United extraction liquid, dry (sal epsom) under reduced pressure removes and desolvates.Preparation of lamina chromatogram (silica gel; Methanol/ethyl acetate, 10/90) handle title compound, HRMS (FAB, M/Z, [M+H]) is about C
28H
35N
30
5The calculated value of+H=494.2655, measured value=494.2653.Preparation example 9 14 Alpha-hydroxies-17-ketone group marcfortine A (formula 12a)
With 14 Alpha-hydroxies-15, (50mg 0.1mmol) is dissolved in THF (5mL) for formula 9a, preparation example 6 ,-78 ℃ of THF solution (1M, 0.7mL) processing of using lithium triethylborohydride down in 16-dehydrogenation-17-ketone group marcfortine A.Under-78 ℃, this mixture is stirred 0.5hr.Add the reaction of methyl alcohol (1mL) all standing, concentrate this mixture.With chromatography (silica gel; Ethanol/methylene, 1/20) handle the solid that generates and get title compound, HRMS (FAB, M/Z, [M+H]) is about C
28H
33N
3O
6The calculated value of+H=508.2447, measured value=508.2437.Preparation example 10 is from 15,16-dehydrogenation-14,17-diketo marcfortine A
(formula 11) preparation 14 Alpha-hydroxies-17-ketone group marcfortine A
(formula 12a) and 14 beta-hydroxyl-17s-ketone group marcfortine A
With 15,16-dehydrogenation-14, (470mg 0.93mmol) is dissolved in THF to 17-diketo marcfortine A for formula 11, preparation example 6,20～25 ℃ of THF solution (1M, 2mL) processing of using lithium borohydride down.This mixture is stirred 2hr, add sodium hydrogen carbonate solution (10%) then.(2 * 20mL) extract this mixture with methylene dichloride.The united extraction thing, dry (sal epsom), steaming desolventizes.Resistates contains and is easy to by chromatography (silica gel; Methanol/ethyl acetate, 1/20) isolating two kinds of epimer mixtures, i.e. 14 Alpha-hydroxies-17-ketone group marcfortine A (90mg, 19%) and 14 beta-hydroxyl-17s-ketone group marcfortine A (94mg, 20%).Preparation example 11 is from 14 Alpha-hydroxies-17-ketone group marcfortine A (formula 12a)
Prepare 14 Alpha-hydroxy marcfortine A (formula 10)
(413mg 0.81mmol) is dissolved in THF (20mL) for formula 12a, preparation example 10,0 ℃ of THF solution (1M, 2.43mL) processing of using borane THF mixture down with 14 Alpha-hydroxies-17-ketone group marcfortine A.This mixture is stirred 2.25hr.Add methyl alcohol (3mL) after mixture stirred 0.5hr.After steaming desolventizes, with chromatography (silica gel; Methanol/ethyl acetate, 1/16) handles resistates and get title compound.Preparation example 12 14,17-diketo marcfortine A (formula 13)
At-78 ℃ of anhydrous methylene chloride (5mL) solution of handling oxalyl chloride (40 μ l) down with methyl-sulphoxide (45 μ l).Stir this mixture down at-78 ℃ and reach 1hr.Drip 14 Alpha-hydroxies-17-ketone group marcfortine A (preparation example 11, methylene dichloride 27mg) (2mL) solution.Stirred this reaction mixture 20 minutes down at-78 ℃.(0.3mL) adds this reaction mixture with triethylamine, makes reaction mixture be warmed to 20～25 ℃ then in 20 minutes.With this mixture yellow soda ash (10%, distribute 10mL) and between the methylene dichloride (10mL).Separate organic layer, dry (sal epsom) concentrates.With chromatography (silica gel; Ethanol/methylene, 1/20) handles resistates and get title compound.HRMS (FAB, M/Z, [M+H]) is about C
28H
31N
3O
6The calculated value of+H=506.2291, measured value=506.2280.Preparation example 13 14 Alpha-hydroxies-14 Beta-methyls-17-ketone group marcfortine A (formula 14a)
At-78 ℃ down with the ethereal solutions of methyl-magnesium-bromides (3M, 0-16mL, 0.48mmol) 14 under handling-78 ℃, 17-diketo marcfortine A (preparation example 12,16mg, 0.032mmol) solution in methylene dichloride (5mL).Stir the mixture that forms down at-78 ℃ and reach 0.5hr.Add yellow soda ash (10%, several) and make the reaction all standing.(10mL) dilutes this mixture with methylene dichloride, and dry (sal epsom) back concentrates.With chromatography (silica gel; Ethanol/methylene, 1/20) handle resistates and 14 Alpha-hydroxies-14 Beta-methyls-17-ketone group marcfortine A (8mg, 50%, R
f=0.25), HRMS (FAB, M/Z, [M+H]) is about C
29H
35N
3O
6The calculated value of+H=522.2604, measured value=522.2620.
Must 14 beta-hydroxies-14 Alpha-Methyls-17-ketone group marcfortine A (1.2mg, 7%, R from this layer
f=0.4), HRMS (FAB, M/Z, [M+H]) is about C
29H
35N
3O
6The calculated value of+H=522.2604, measured value=522.2630.When using THF replacement methylene dichloride as reaction solvent, 6: 1 ratios of product that obtain are like this increased to more than 50: 1, productive rate increases to 80%.Preparation example 14 14 Alpha-hydroxies-14 Beta-methyl marcfortine A (formula 15)
At 0 ° of THF solution (1M, 0.03mL, 0.03mmol) processing 14 Alpha-hydroxies-14 Beta-methyls-17-ketone group marcfortine A (preparation example 13,5mg, 0.01mmol) solution in THF (5mL) of using lithium aluminum hydride down.Stir this mixture down at 0 ° and reach 0.5hr, add sodium hydrogen carbonate solution (10%) then.(2 * 5mL) extract this mixture with methylene dichloride.The united extraction thing, dry (sal epsom) back is steamed and is desolventized.Preparation property TLC (silica gel; Ethanol/methylene, 1/20) after handling title compound, HRMS (FAB, M/Z, [M+H]) is about C
29H
37N
3O
5The calculated value of+H=508.2811, measured value=508.2816.Preparation example 15 14-ketone group marcfortine A (formula 16)
Handle the solution of oxalyl chloride (150 μ l) in anhydrous methylene chloride (20mL) with DMSO (170 μ l) down at-78 ℃.Stir this mixture down at-78 ℃ and reach 1hr.Drip 14 Alpha-hydroxy marcfortine A (preparation example 11,110mg) solution in methylene dichloride (5mL).Under-78 ℃, this reaction mixture was stirred 20 minutes.In reaction mixture, add TEA (1mL), during 20 minutes, make this reaction mixture be warmed to 20～25 ℃.Yellow soda ash (10%, distribute this mixture 20mL) and between the methylene dichloride (20mL).Separate organic layer, dry (sal epsom) back concentrates.With chromatography (silica gel; Ethanol/methylene, 1/25) handle resistates and get title compound, HRMS (FAB, M/Z, [M+H]) is about C
28H
33N
3O
5The calculated value of+H=492.2498, measured value=492.2510.Preparation example 16 14 beta-hydroxy marcfortine A (formula 17)
Handle 14-ketone group marcfortine A (preparation example 15,10mg) solution in methyl alcohol (2mL) with sodium borohydride (5mg) down at 0 °.Stir this mixture down at 0 ° and reach 0.5hr, add sodium hydrogen carbonate solution (10%) then.(2 * 10mL) extract this mixture with methylene dichloride.The united extraction thing, dry (sal epsom) back is steamed and is desolventized.With preparation property TLC (silica gel, methanol/ethyl acetate, 1/16) handle title compound, HRMS (FAB, M/Z, [M+H]) is about C
28H
35N
3O
5The calculated value of+H=494.2655, measured value=494.2653.Preparation example 17 14 Alpha-hydroxy marcfortine A N-oxide compounds (formula 18)
Between using under 0 °-chlorine peroxybenzoic acid (15mg) processing 14 Alpha-hydroxy marcfortine A (preparation example 11,15mg) solution in methylene dichloride (3mL).Stir this mixture 0.5hr down at 0 °, use TEA (30 μ l) to handle then, concentrate.With preparation property TLC (silica gel; Ethanol/methylene, 1/8) handle title compound, HRMS (FAB, M/Z, [M+H]) is about C
28H
35N
3O
6The calculated value of+H=510.2604, measured value=510.2615.Preparation example 18 14 Alpha-hydroxies-14 β-ethyl marcfortine A (formula 19)
Down (3M, 0.15mL 0.45mmol) handle-78 ℃ 14-ketone group marcfortine A (preparation example 15,25mg, THF 0.05mmo1) (5mL) solution with the ethereal solutions of ethylmagnesium bromide at-78 ℃.Stir the gained mixture down at-78 ℃ and reach 0.5hr.During 20 minutes, make reaction mixture be warmed to 20～25 ℃.Add yellow soda ash (10%, several) and make the reaction all standing.(10mL) dilutes this mixture with methylene dichloride, and dry (sal epsom) back concentrates.With chromatography (silica gel; Ethanol/methylene, 1/20) handle resistates and get title compound, HRMS (FAB, M/Z, [M+H]) is about C
30H
39N
3O
5The calculated value of+H=522.2968, measured value=522.2983.Preparation example 19 prepares 14 Beta-methyl marcfortine A from 14 Alpha-hydroxies-14 Beta-methyl marcfortine A
((66mg is in THF 0.14mmol) (2mL) solution for formula 15, preparation example 14 0.5mmol) to be added drop-wise to 14 Alpha-hydroxies-14 Beta-methyl marcfortine A for 0.5M, 1mL with the toluene solution of two (trimethyl silyl) ammonification potassium under-78 ℃.The mixture of formation is warmed to-40 ℃.This reaction mixture is cooled to-78 ℃, stirred 15 minutes, (0.094mL, THF 0.7mmol) (2mL) solution is handled by dripping chloro thion phenyl formate then.Remove the dry ice bath after 10 minutes.Further add sodium bicarbonate behind the reaction 3hr and make the reaction all standing.(2 * 25mL) extract this mixture with methylene dichloride.United extraction liquid, dry (sal epsom) back concentrate thick material.Get 14 α-O-phenoxy group thiocarbonyl group-14 Beta-methyl marcfortine A with preparation property TLC (silica gel, ethyl acetate) purifying.
To 14 α-O-phenoxy group thiocarbonyl group-14 Beta-methyl marcfortine A (64mg, 0.1mmol) in the solution of toluene (5mL), add AIBN (2,2 '-the azepine bis-isobutyronitrile, 3.3mg), then add tri-butyl tin hydride (54 μ l, 0.2mmol).With this mixture backflow 3hr.After steaming desolventizes, by preparation property TLC (silica gel; Ethyl acetate) the purifying resistates gets 14 Beta-methyl marcfortine A.Another synthesis method of preparation example 20 17-ketone group marcfortine A (formula 7)
Under refluxing, during one hour, toward marcfortine A (65g, 0.136mol) and sodium bicarbonate (137g, 1.63mol) in tetrahydrofuran (THF) (THF, 2L) and drip iodine (206g, 0.81mol) solution in THF (1.25L) in the solution of water (1.25L).(also can under 20～25 ℃, this mixture be stirred 16 hours).After letting alone to slowly cool to 20～25 ℃ (2.5hr), (1.5L) makes the reaction all standing with saturated sodium thiosulfate solution, and (2 * 1L) extract to use ethyl acetate again.The merging organic layer with saturated sodium thiosulfate (1L) solution washing, dry (sal epsom), filters, and evaporation then a dry night in vacuum drying oven (65 ℃), gets the rough 17-ketone group of 62g marcfortine A (formula 7), NRM (300MHz, CDCl
3) 7.68,6.80,6.70,6.32,4.90,3.75,3.23,3.09,2.80,2.65,2.49-2.21,2.08,1.98-1.45,1.46,1.44,1.09 and 0.90 δ.
Also can use iodine monochloride (ICl) and replace iodine.Preparation example 21 16-two sulfur phenenyls-17-ketone group marcfortine A (formula 20)
Under-78 ℃ by sleeve pipe with rough 17-ketone group marcfortine A (preparation example 20,5g, 10.2mmol) adding LDA solution in THF (150mL), this LDA solution be by among the THF under 0 ° (100mL) with n-Butyl Lithium (1.6M, 24.8mL, 0.04mmol) be added drop-wise to Diisopropylamine (5.7mL, 0.041mol) in and the preparation.In 1hr, allow reaction mixture be warmed to-50 ℃ lentamente.(4.4g 0.02mol) handles the mixture that forms to use phenyl disulfide then.Use saturated sodium bicarbonate solution (100mL) to make the reaction all standing at once, use methylene dichloride (300mL) to extract again.Dry (sal epsom) organic phase concentrates (8g), with chromatography (silica gel, 120g; Ethyl acetate/hexane, 60/40) handle title compound, MS (FAB)=708 (M
++ H); NMR (300MHz, CDCl
3) 7.74,7.71,7.64,7.45-730,6.81,6.72,6.32,4.91,3.70,3.16,3.01,2.75,2.53,2.35,2.15-1.50,1.47,1.45,1.06 and 0.82 δ.Preparation example 22 16-thiophenyl-16-benzenesulfinyl (sulfoxyphenyl)-17-ketone group marcfortine A (formula 21)
In-78 ℃ of following nitrogen atmospheres, toward 16-two sulfur phenenyls-17-ketone group marcfortine A (preparation example 21,10g, 14mmol) in the solution of methylene dichloride (250mL), drip between-chlorine peroxybenzoic acid (64%, 4.2g methylene dichloride 15.5mmol) (200mL) solution reaches 15 minutes.Use saturated sodium thiosulfate (200mL) to make the reaction all standing at once,, use methylene dichloride (200mL) to extract again with saturated sodium bicarbonate (200mL) dilution.Dry (sal epsom), then under reduced pressure concentrate title compound, NMR (300MHz, CDCl
3) 8.0-7.29,6.80,6.70,6.31,4.90,3.68,3.41,3.14,3.07,2.82,2.80-2.65,2.16,2.05-1.1,1.47,1.43,0.96 and 0.83 δ.Preparation example 23 16-thiophenyls-15,16-dehydrogenation-17-ketone group marcfortine A (formula 22)
With thick 16-thiophenyl-16-benzenesulfinyl-17-ketone group marcfortine A (formula 21; preparation example 22 11g) refluxed 45 minutes in toluene (250mL), was cooled to 20～25 ℃; with saturated sodium bicarbonate (300mL) dilution, use ethyl acetate (300mL) to extract again.With organic layer drying (sal epsom), concentrate title compound, MS (FAB)=598 (M
++ H); HRMS (M/Z, M
++ H) C
34H
35N
3O
5S+H
1, calculated value=598.2376, observed value=598.2387; NMR (300MHz, CDCl
3) 8.18,7.55-7.45,7.29-7.45,6.83,6.70,6.34,5.92,4.91,3.87,3.30,3.21,3.08,2.80,2.35,2.10,2.03,1.78,1.46,1.44,1.11 and 0.88 δ.Preparation example 24 16-benzenesulfinyl-15,16-dehydrogenation-17-ketone group marcfortine A (formula 23)
Under-78 ℃, toward thick 16-thiophenyl-15,16-dehydrogenation-17-ketone group marcfortine A (formula 22, preparation example 23,10.6g) in the solution of methylene dichloride (300mL), drip between-the chlorine peroxybenzoic acid (64%, methylene dichloride 2.8g) (125mL) solution.Make the reaction all standing with saturated sodium thiosulfate (300mL) and saturated sodium bicarbonate (300mL), be extracted into methylene dichloride (300mL) then.With organic layer drying (sal epsom), filter the back concentrate title compound, NMR (300MHz, CDCl
3) 7.75-7.3,6.81,6.75-6.6,6.31,4.90,3.78-3.58,3.22,2.98,2.88-2.45,2.12-1.55,1.46,1.44,1.12 and 0.88 δ.
Preparation example 25 14 Alpha-hydroxies-15,16-dehydrogenation-17-ketone group marcfortine A (formula 9a)
Toward thick 16-benzenesulfinyl-15, and 16-dehydrogenation-17-ketone group marcfortine A (formula 23, preparation example 24, methanol aqueous solution 13g) (10/1,300mL) the middle diethylamine (15mL) that adds.Make reaction mixture be cooled to 20～25 ° behind the backflow 0.5hr, water (450mL) dilution is extracted into methylene dichloride (500mL).Dry (sal epsom) then concentrates, with chromatography (silica gel, 130g; Acetone/methylene dichloride 30/70) handle title compound.Preparation example 26 14 Alpha-hydroxies-14 β-vinyl marcfortine A (formula 30)
Down (1M, 4.0mL 4mmol) handle-78 ° 14-ketone group marcfortine A (formula 16, preparation example 15,200mg, 0.4mmol) solution in THF (5mL) with the THF solution of vinyl bromination magnesium at-78 °.Stir the mixture that forms down at-78 ° and reach 2hr, be warmed to 20～25 ° again.Stir 2hr down at 20～25 °.Interpolation yellow soda ash (10%, 3mL) make the reaction all standing.(30mL) dilutes this mixture with methylene dichloride, and with the saturated ammonium chloride solution washing, dry (sal epsom) back concentrates.With chromatography (silica gel; Hexane/acetone, 6/4) handle resistates and title compound, NMR (300MHz, CDCl
3) 7.86,6.78﹠amp; 6.67,6.32,6.58,5.43,5.18,4.89,3.7,3.11,2.95,2.8-1.5,1.44,1.08 and 0.82 δ; MS (FAB, M/Z, [M+H])=520.Preparation example 27 14 Alpha-hydroxies-14 Beta-methyl marcfortine A N-oxide compound (formula 32)
Under 0 °, between using-chlorine peroxybenzoic acid (20mg) processing 14 Alpha-hydroxy marcfortine A (preparation example 11,30mg) solution in methylene dichloride (3mL).Stir this mixture 0.5hr, then sodium bicarbonate aqueous solution (5%, distribute 10mL) and between the methylene dichloride (20mL).After the layering, extract water layer with methylene dichloride (10mL).Organic extracting solution dried over mgso after the merging is filtered, and evaporation under 0 ° and decompression is handled with triethylamine (30 μ l), concentrate title compound, NMR (300MHz, CD
3OD) 6.91﹠amp; 6.70,6.36,4.91,4.08﹠amp; 3.76,3.5-3.1,3.12,2.8-1.6,1.46﹠amp; 1.44,1.50 and 0.93 (s, 3H) δ.Preparation example 28 14 Alpha-hydroxies-15 Alpha-Methyl marcfortine A (formula 35)
(preparation example 32,90mg 0.18mmol) are dissolved in THF (10mL), and (12M 0.18mL) handles with borane dimethyl sulfide mixture down at 0 ° with 14 Alpha-hydroxies-15 Alpha-Methyls-17-ketone group marcfortine A.Stir this mixture down at 0 ° and reach 2hr, add methyl alcohol (0.4mL) then, stir 1hr again.After boiling off solvent, with chromatography (silica gel; Acetone/methylene dichloride, 30/70) handles resistates and get title compound, NMR (300MHz, CDCl
3) 8.39,6.79﹠amp; 6.70,6.36,4.91,3.81,3.67,3.03,3.11,2.68﹠amp; 1.86,2.7-1.2,1.44,1.02,1.11 and 0.85 δ; HRMS (FAB, M/Z, [M+H]) is about C
29H
37N
3O
5The calculated value of+H=508.2811, measured value=508.2840.Preparation example 29 14,17-diketo-15 Alpha-Methyl marcfortine A (formula 36)
Handle the solution of oxalyl chloride (40 μ l) in anhydrous methylene chloride (5mL) with DMSO (45 μ l) down at-78 ℃.Stir this mixture down at-78 ℃ and reach 1hr.Drip 14 Alpha-hydroxies-15 Alpha-Methyls-17-ketone group marcfortine A (preparation example 33,27mg) solution in methylene dichloride (2mL).Stirred this reaction mixture 20 minutes down at-78 °.In this reaction mixture, add TEA (0.3mL), in 20 minutes, allow this reaction mixture be warmed to 20～25 °.With this mixture yellow soda ash (10%, distribute 10mL) and between the methylene dichloride (10mL).Organic layer drying (sal epsom) back is concentrated.With chromatography (silica gel; Ethanol/methylene, 1/20) handle resistates and get title compound, HRMS (FAB, M/Z, [M+H]) is about C
28H
31N
3O
6The calculated value of+H=506.2291, measured value=506.2280.Preparation example 30 14 Alpha-hydroxies-14 Beta-methyl-15 Alpha-Methyls-17-ketone group marcfortine A (formula 37)
Under-78 °, with the ethereal solution of methyl-magnesium-bromide (3M, 0.2mL, 0.6mmol) handle-78 ° 14,17-diketo-15 Alpha-Methyl marcfortine A (preparation example 29,25mg, 0.05mmol) solution in methylene dichloride (5mL).Stir the mixture that forms down at-78 ° and reach 0.5hr.Add yellow soda ash (10%, several) and make the reaction all standing.(10mL) dilutes this mixture with methylene dichloride, and dry (sal epsom) back concentrates.With chromatography (silica gel; Ethanol/methylene, 4/96) handle resistates and title compound, NMR (300 MHz, CDCl
3) 8.13,6.78,6.70,6.33,4.91,3.75,3.16,3.05,2.78,2.68-2.57,2.42-2.0,1.64,1.45,1.44,1.11,1.04 and 0.92 δ.Preparation example 31 14 Alpha-hydroxies-14 Beta-methyl-15 Alpha-Methyl marcfortine A (formula 38)
(preparation example 30,15mg 0.028mmol) are dissolved in THF (10mL), and then (10M 0.02mL) handles with borane dimethyl sulfide mixture down at 0 ° with 14 Alpha-hydroxies-14 Beta-methyl-15 α Alpha-Methyl-17-ketone group marcfortine A.Stir this mixture down at 0 ° and reach 2hr, add methyl alcohol (0.4mL) then, stir 1hr again.After boiling off solvent, with chromatography (silica gel; Acetone/methylene dichloride, 30/70) handles resistates and get title compound, NMR (300MHz, CDCl
3) 7.82,6.79,6.67,6.33,4.90,3.65,3.09,2.98,2.69,2.60-2.22,2.06,1.87,1.85-1.75,1.44,1.43,1.10,0.94 and 0.86 δ.Preparation example 32 14 Alpha-hydroxies-15 Alpha-Methyls-17-ketone group marcfortine A (formula 34)
Under 20～25 °, handle 14 Alpha-hydroxies-15,16-dehydrogenation-17-ketone group marcfortine A (formula 9a, 300mg) mixture in THF (12mL) with methyl-magnesium-bromide solution (3M, 1.0mL, 5 equivalents).Mixture backflow 1.5hr with forming is cooled to 20～25 ° then.Add saturated ammonium chloride (3mL) and make the reaction all standing.(30mL) dilutes this mixture with methylene dichloride, and with the saturated ammonium chloride solution washing, dry back concentrates on sal epsom.With this enriched material chromatography (silica gel; Ethanol/methylene, 1/20) handle title compound, NMR (300MHz, CDCl
3) 7.90,6.80﹠amp; 6.70,6.32,4.89,4.36,3.74,3.20,3.06,2.78﹠amp; 2.10,2.5-1.8,1.46﹠amp; 1.44,1.13,1.12 and 0.88 δ.
Also can use lithium dimethylcuprate reagent preparation title compound.Cupric iodide under 0 ° (0.4g, 0.002mol)/drip among the THF lithium methide (1.4M, 9mL, 0.013mol).The mixture that forms was stirred 15 minutes, drip 14 Alpha-hydroxies-15 down at 0 ° then, (0.001mol) solution in THF (12mL) is handled for formula 9a, 0.Sg in 16-dehydrogenation-17-ketone group marcfortine A.This mixture stirring after 15 minutes, with the reaction of saturated ammonium chloride (25mL) all standing, is extracted into ethyl acetate (30mL) again.Dry organic extraction on sal epsom, filter the back concentrate thick material, with chromatogram arrangement (4mm plate; Ethanol/methylene, 4/96) purifying gets title compound.Preparation example 33 14,17-diketo-15 Alpha-Methyl marcfortine A (formula 36)
Handle the mixture of oxalyl chloride (40 μ l) in anhydrous methylene chloride (5mL) with DMSO (45 μ l) down at-78 °.Stir this mixture down at-78 ° and reach 1hr.Drip 14 Alpha-hydroxies-15 Alpha-Methyls-17-ketone group marcfortine A (preparation example 33,27mg) solution in methylene dichloride (2mL).Under-78 ℃, this reaction mixture was stirred 20 minutes.In reaction mixture, add triethylamine (0.3mL), in 20 minutes, make this reaction mixture be warmed to 20～25 °.Yellow soda ash (10%, distribute this mixture 10mL) and between the methylene dichloride (10mL).Be separated, organic layer dry back on sal epsom is concentrated.With chromatography (silica gel; Ethanol/methylene, 1/20) handle this enriched material and title compound, ([M+H] is about C for FAB, M/Z for HRMS
28H
31N
3O
6The calculated value of+H=506.2291, measured value=506.2280.Embodiment 1 24, and 25,26,27,28-five removes first marcfortine A (II)
With marcfortine A (I, 8.5g, 0.018mol) be dissolved in formic acid (95% purity, 100mL).Under 20～25 °, this mixture is stirred 16hr.Remove volatile constituent, resistates heavily is dissolved in methyl alcohol (100mL).Concentrate this mixture, by chromatography (silica gel; Ethanol/methylene, 10/90) the purifying resistates gets title compound, the NMR of selection (300MHz, CDCl
3+ CD
3OD) 0.80,1.09,1.4～2.0,2.2～2.8,3.10,3.87,6.52 and 6.61 δ; MS (FAB, M/Z, [MtH
+])=412.Embodiment 2 7-O-isopentene groups (Prenyl)-24,25,26,27,28-five removes first marcfortine A (III)
Toward the 4-bromo-2-methyl-2-butene (1.0ml that in acetone (40mL), has stirred 5 minutes, 8.7mmol) and potassiumiodide (1.44g, add in 8.7mmol) salt of wormwood (1.6g, 11.7mmol), then drip 24,25,26,27,28-five goes first marcfortine A (II, embodiment 1,1.2g, 0.0029mol) mixed solution in acetone (10mL/6mL).This reaction mixture is stirred 0.25hr, and (100mL) makes the reaction all standing with saturated sodium bisulfite solution, is extracted into ethyl acetate (100mL) again.Dry organic layer on sal epsom, filter the back concentrating under reduced pressure and title compound, NMR (400MHz, CDCl
3) 7.90,6.79,6.57,5.50,4.49,3.70,3.10,2.99,2.66,1.83,2.55-2.5,2.39,2.29,2.14,1.95-1.30,1.76,1.61,1.10 and 0.81 δ.Embodiment 3 7-O-(2 ', 3 '-epoxy-3 '-methyl) butyl-24,25,26,27,28-five removes first marcfortine A (IV)
20～25 ° down toward 7-isopentene groups-24,25,26,27,28-five go first marcfortine A (III, embodiment 3,1.4g, 2.9mmol) in the solution of methylene dichloride (30mL) disposable adding 3-chlorine peroxybenzoic acid (2.4g, 8.3mmol).After stirring 0.5hr, add sodium bisulfite (6g is in 50mL water), continue to stir 0.5hr.With sodium bicarbonate (saturated, 100mL) make the reaction all standing, be extracted into ethyl acetate (100mL).Separate organic extraction, dry on sal epsom, filter the back concentrate the title compound of non-enantiomer mixture form, be not further purified and use this compound, NMR (400MHz, CDCl
3) 8.52,8.44,6.82,6.59,4.56-4.47,3.92-3.84,3.69,3.26-3.14,3.11,3.01,2.70-2.55,3.39,2.30,2.15,1.98-1.50,1.41,1.40-1.20,1.10,0.82 and 0.81 δ.Embodiment 4 25-hydroxyls-24,25-dihydro marcfortine A (V)
In the nitrogen atmosphere under 20～25 °, past 7-O-(2 ', 3 '-epoxy-3 ＇-methyl)-butyl-24,25,26,27,28-five removes first marcfortine A, and (IV, 1.2g 2.4mmol) drip tin chloride (IV) (0.2mL) in the mixed solution of THF (30mL).After stirring 0.25hr, (10% aqueous solution 50mL) makes the reaction all standing, is extracted into ethyl acetate (100mL) with Potassium monofluoride.Separate organic extraction, dry on sal epsom, filter the back concentrate the title compound of non-enantiomer mixture form, be not further purified and use this compound.The NMR (400MHz, the CDCl that select
3) 8.17,7.87,6.80-6.45,4.40,4.25,4.05-3.90 and 3.15 δ.
Embodiment 5 24,25-dihydro-25-oxo marcfortine A (VI)
Under-78 °, slowly drip methylene dichloride (1mL) solution of DMSO (0.06mL) in methylene dichloride (5mL) solution of oxalyl chloride (0.045mL).After stirring 0.25hr under-78 °, drip 25-hydroxyl-24, (V, embodiment 4,60mg, 0.12mmol) solution in methylene dichloride (1mL) for 25-dihydro marcfortine A.This reaction mixture is stirred 0.25hr, use TEA (0.25mL) to make the reaction all standing then, stir 0.25hr down at 20～25 ° again.Sodium bicarbonate (saturated, distribute this reaction mixture 25mL) and between the ethyl acetate (25mL).The separation organic extraction, dry on sal epsom, filter, concentrate back chromatography (silica gel; Ethanol/methylene (5/95)) handle title compound, NMR (400MHz, CDCl
3) 7.45,6.77,6.64,4.89,3.70,3.11,3.02,2.70,1.85,2.65,2.40,2.31,2.15,1.95-1.85,1.80-1.0,1.53,1.51,1.13 and 0.85 δ; HRMS (FAB, M/Z, [M+H]) is about C
28H
35N
3O
5The calculated value of+H=494.2655, measured value=494.2662.Embodiment 6 24,25-dihydro-25-methylene radical marcfortine A (VII)
Under 20～25 °, toward first base three phenyl phosphonium bromides (70mg, drip in ether 0.2mmol) (5mL) solution n-Butyl Lithium (1.6M in hexane, 0.13mL, 0.2mmol).Under nitrogen atmosphere and 20～25 °, the gained mixture was stirred 5 minutes, drip 24 then, and 25-dihydro-25-oxo marcfortine A (VI, embodiment 5,25mg, THF 0.05mmol) (5mL) solution is handled.This reaction mixture is stirred 0.25hr, and water (25mL) makes the reaction all standing, is extracted into ethyl acetate (25mL).The separation organic extraction, dry on sal epsom, filter, concentrate back chromatography (silica gel; Acetone/hexane, 40/60) handle title compound, NMR (400 MHz, CDCl
3) 7.67,6.72,6.47,5.24,5.08,4.90,4.77,3.60,2.30,3.04,2.96,2.60﹠amp; 1.78,2.58-2.52,2.23,2.08,1.88-1.20,1.44﹠amp; 1.42 and 1.10﹠amp; 0.80 δ; HRMS (FAB, M/Z, [M+H]) is about C
29H
37N
30
4The calculated value of+H=492.2862, measured value=492.2858.Embodiment 7 24,25-epoxy marcfortine A (VIII)
With marcfortine A (I, 0.25g, 0.5mmol) and-(1.4mmol) mixture in methylene dichloride (25mL) stirs 16hr to the chlorine peroxybenzoic acid for purity 60%, 0.4g.Handle this reaction mixture with sodium bisulfite (1.1g is in 15mL water), stir 0.5hr, and the usefulness sodium bicarbonate (saturated, 100mL) make the reaction all standing, be extracted into methylene dichloride (25mL).Dry organic extraction on sal epsom filters, and concentrates back chromatography (silica gel; Acetone/methylene dichloride, 40/60) must be as the title compound of the non-enantiomer mixture that can not be split, the NMR of selection (400MHz, CDCl
3) 8.01﹠amp; 7.86,6.80﹠amp; 6.58,5.36-5.30﹠amp; 3.00-2.97,3.70,3.12,2.69﹠amp; 1.85 and 2.40 δ.Embodiment 8 24,25-dihydro-25-methylene radical paraheroquamide A (VII)
By the general operation of embodiment 1～6 and do nonessential change, but the initial PPPA that uses, title compound.Embodiment 9 14 Alpha-hydroxies-14 Beta-methyl-24,25-dihydro-25-methylene radical marcfortine A (VII)
By the general operation of embodiment 1～6 and do nonessential change, but initial usefulness 14 Alpha-hydroxies-14 Beta-methyl marcfortine A, title compound.Embodiment 10 14 Alpha-hydroxies-15 alpha-methyl-2 4,25-dihydro-25-methylene radical marcfortine A (VII)
By the general operation of embodiment 1～6 and do nonessential variation, but initial usefulness 14 Alpha-hydroxies-15 Alpha-Methyl marcfortine A, title compound.Embodiment 11 24,25-epoxy paraheroquamide A (VIII)
By the general operation of embodiment 7 and do nonessential variation, but the initial paraheroquamide A that uses, title compound.Embodiment 12 14 Alpha-hydroxies-14 Beta-methyl-24,25-epoxy marcfortine A (VIII)
By the general operation of embodiment 7 and do nonessential variation, but initial usefulness 14 Alpha-hydroxies-14 Beta-methyl marcfortine A, title compound.Embodiment 13 14 Alpha-hydroxies-15 alpha-methyl-2 4,25-epoxy marcfortine A (VIII)
By the general operation of embodiment 7 and do nonessential change, but initial usefulness 14 Alpha-hydroxies-15 Alpha-Methyl marcfortine A, title compound.Embodiment 14 N-(18a)-demethylation-2-deoxidation paraheroquamide A (method 1)
The method that proposes by international open WO92/00300, with N-(18a)-demethylation paraheroquamide A (50mg, 0.1mmol) be dissolved in glycol dimethyl ether (glyme, 5mL) and water (0.5mL).(0.15g 6.9mmol) handles this mixture, and being heated to refluxes reaches 5hr to use lithium borohydride then.(25mL) makes the reaction mixture quenching with salt solution, is extracted into ethyl acetate.Separate organic phase, dry on sal epsom, filter the back and concentrate.Get N-(18a)-demethylation-2-deoxidation paraheroquamide A with silica gel chromatography purifying enriched material.
Embodiment 15 N-(18a)-demethylation-2-deoxidation paraheroquamide A (method 2)
Can prepare N-(18a)-demethylation-2-deoxidation paraheroquamide A like this, the promptly initial paraheroquamide A that uses is transformed into 2-deoxidation paraheroquamide A by the method that proposes among the WO97/03988 with it.The graceful subspecies of cunninghamella echinulata (Cunninghamellaechinulata subsp.elegans) that DMF (0.4mL) solution of 2-deoxidation paraheroquamide A (10mg) is added to strong growth in the 500mL wide neck flask (UUC7602) or cunninghamella echinulata (C.echinulata) (UC7330) in the culture (100mL).Cultivate under 28 °, decide according to culture, continuous oscillation 1～3 day gets N-(18a)-demethylation-2-deoxidation paraheroquamide A.By thoroughly extracting with methylene dichloride, centrifugal, under reduced pressure realize separating except that desolvating.Analyze residual substance by TLC and HPLC.Carry out purifying with various chromatographic techniques, finish determining structure by NMR and MS.
Table ATable A (continuing)
Table A (continuing)Table B
Claims (15)
1. the 25-methylene compound of formula (VII)
Wherein: (I) marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-H, and
R14 βBe-H,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H; (II) paraheroquamide A
(a) n is 0,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe-CH
3,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H; (III) 14-hydroxyl-14-alkyl marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe C
1-C
4Alkyl,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H; (IV) 14-hydroxyl-15-alkyl marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe-H,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe C
1-C
4Alkyl, and R
15 βBe-H and pharmaceutically acceptable salt thereof.
2. the methylene compound of the formula of claim 1 (VII), wherein this pharmaceutically acceptable salt is the salt that is selected from following acid, i.e. methylsulfonic acid, hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, phenylformic acid, citric acid, tartrate, fumaric acid, toxilic acid, CH
3-(CH
2)
n-COOH, wherein n is 0～4, HOOC-(CH
2)
n-COOH, wherein n is with above-mentioned definition.
3. the methylene compound of the formula of claim 1 (VII), wherein n
1Be 0.
4. the methylene compound of the formula of claim 3 (VII), it is
24,25-dihydro-25-methylene radical paraheroquamide A.
5. the methylene compound of the formula of claim 1 (VII), wherein n
1Be 1.
6. the methylene compound of the formula of claim 5 (VII), it is selected from down the group material:
24,25-dihydro-25-methylene radical marcfortine A,
14 Alpha-hydroxies-14 Beta-methyl-24,25-dihydro-25-methylene radical marcfortine A and
14 Alpha-hydroxies-15 alpha-methyl-2 4,25-dihydro-25-methylene radical marcfortine A.
7. the methylene compound of the formula of claim 6 (VII), it is 24,25-dihydro-25-methylene radical marcfortine A.
8. 24 of formula (VIII), the 25-epoxy compounds
Wherein: (I) marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-H, and R
14 βBe-H,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H; (II) paraheroquamide A
(a) n is 0,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe-CH
3,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H; (III) 14-hydroxyl-14-alkyl marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe C
1-C
4Alkyl,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe-H, and R
15 βBe-H; (IV) 14-hydroxyl-15-alkyl marcfortine A
(a) n is 1,
(b) R
14Be R
14 α: R
14 β, R wherein
14 αBe-OH, and R
14 βBe-H,
(c) R
15Be R
15 α: R
15 β, R wherein
15 αBe C
1-C
4Alkyl, and R
15 βBe-H and pharmaceutically acceptable salt thereof.
9. 24 of the formula of claim 8 (VIII), the 25-epoxy compounds, wherein this pharmaceutically acceptable salt is the salt that is selected from following acid, i.e. methylsulfonic acid, hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, phenylformic acid, citric acid, tartrate, fumaric acid, toxilic acid, CH
3-(CH
2)
n-COOH, wherein n is 0～4, HOOC-(CH
2)
n-COOH, wherein n is with above-mentioned definition.
10. 24 of the formula of claim 8 (VIII), 25-epoxy compounds, wherein n
1Be 0.
11. 24 of the formula of claim 10 (VIII), the 25-epoxy compounds, it is
24,25-epoxy paraheroquamide A.
12. 24 of the formula of claim 8 (VIII), 25-epoxy compounds, wherein n
1Be 1.
13. 24 of the formula of claim 12 (VIII), the 25-epoxy compounds, it is selected from down the group material:
24,25-epoxy marcfortine A,
14 Alpha-hydroxies-14 Beta-methyl-24,25-epoxy marcfortine A and
14 Alpha-hydroxies-15 alpha-methyl-2 4,25-epoxy marcfortine A.
14. 24 of the formula of claim 13 (VII), the 25-epoxy compounds, it is 24,25-epoxy marcfortine A.
15.N-(18a)-demethylation-2-deoxidation paraheroquamide A and pharmaceutically acceptable salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2598396P | 1996-09-09 | 1996-09-09 | |
| US60/025,983 | 1996-09-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1230188A true CN1230188A (en) | 1999-09-29 |
Family
ID=21829160
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97197774A Pending CN1230188A (en) | 1996-09-09 | 1997-09-05 | 25-methylene and 24,25-epoxy marcfortines and paraheroquamides |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5886180A (en) |
| EP (1) | EP0929555A1 (en) |
| JP (1) | JP2001500494A (en) |
| KR (1) | KR20000068471A (en) |
| CN (1) | CN1230188A (en) |
| AU (1) | AU4094597A (en) |
| BR (1) | BR9711721A (en) |
| CA (1) | CA2264052A1 (en) |
| CO (1) | CO4900069A1 (en) |
| CZ (1) | CZ51999A3 (en) |
| HU (1) | HUP0000264A2 (en) |
| NO (1) | NO991123L (en) |
| PE (1) | PE98998A1 (en) |
| PL (1) | PL332044A1 (en) |
| SK (1) | SK27499A3 (en) |
| TR (1) | TR199900496T2 (en) |
| WO (1) | WO1998009971A1 (en) |
| ZA (1) | ZA976761B (en) |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5075307A (en) * | 1987-07-28 | 1991-12-24 | Merck & Co., Inc. | Paraherquamide and dihydroparaherquamide as antihelminthic agents |
| US4873247A (en) * | 1987-11-27 | 1989-10-10 | Goegelman Robert T | Derivatives of paraherquamide isolated from a fermentation broth active as antiparasitic agents |
| US4978656A (en) * | 1988-08-12 | 1990-12-18 | Merck & Co., Inc. | Synthetic derivatives of paraherquamide |
| US4866060A (en) * | 1988-08-19 | 1989-09-12 | Merck & Co., Inc. | Use of the natural product marcfortines as antiparasitic agents |
| US4923867A (en) * | 1988-08-24 | 1990-05-08 | Merck & Co., Inc. | Synthetic marcfortine derivatives useful as antiparasitic agents |
| NZ233043A (en) * | 1989-03-30 | 1992-09-25 | Merck & Co Inc | Anthelmintic heterocyclic compounds prepared by action of cunninghamella blakesleeana on (dihydro)paraherquamide |
| IE904606A1 (en) * | 1989-12-21 | 1991-07-03 | Beecham Group Plc | Novel products |
| GB9014194D0 (en) * | 1990-06-26 | 1990-08-15 | Pfizer Ltd | Antiparasitic agents |
| WO1992022555A1 (en) * | 1991-06-17 | 1992-12-23 | Beecham Group Plc | Paraherquamide derivatives, precursor thereof, processes for their preparation, microorganism used and their use as antiparasitic agents |
| TW410227B (en) * | 1993-06-16 | 2000-11-01 | Upjohn Co | 14-substituted marcfortines and derivatives useful as antiparasitic agents |
| MY113806A (en) * | 1995-07-21 | 2002-05-31 | Upjohn Co | Antiparasitic marcfortines and paraherquamides |
-
1997
- 1997-07-29 ZA ZA976761A patent/ZA976761B/en unknown
- 1997-08-06 PE PE1997000686A patent/PE98998A1/en not_active Application Discontinuation
- 1997-09-05 PL PL97332044A patent/PL332044A1/en unknown
- 1997-09-05 SK SK274-99A patent/SK27499A3/en unknown
- 1997-09-05 CO CO97051585A patent/CO4900069A1/en unknown
- 1997-09-05 CZ CZ99519A patent/CZ51999A3/en unknown
- 1997-09-05 WO PCT/US1997/015309 patent/WO1998009971A1/en not_active Application Discontinuation
- 1997-09-05 US US08/924,347 patent/US5886180A/en not_active Expired - Fee Related
- 1997-09-05 EP EP97938665A patent/EP0929555A1/en not_active Withdrawn
- 1997-09-05 CN CN97197774A patent/CN1230188A/en active Pending
- 1997-09-05 KR KR1019997001856A patent/KR20000068471A/en not_active Application Discontinuation
- 1997-09-05 TR TR1999/00496T patent/TR199900496T2/en unknown
- 1997-09-05 CA CA002264052A patent/CA2264052A1/en not_active Abandoned
- 1997-09-05 HU HU0000264A patent/HUP0000264A2/en unknown
- 1997-09-05 AU AU40945/97A patent/AU4094597A/en not_active Abandoned
- 1997-09-05 JP JP10512769A patent/JP2001500494A/en active Pending
- 1997-09-05 BR BR9711721A patent/BR9711721A/en not_active Application Discontinuation
-
1999
- 1999-03-08 NO NO991123A patent/NO991123L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR20000068471A (en) | 2000-11-25 |
| US5886180A (en) | 1999-03-23 |
| NO991123L (en) | 1999-05-07 |
| ZA976761B (en) | 1999-01-29 |
| CA2264052A1 (en) | 1998-03-12 |
| WO1998009971A1 (en) | 1998-03-12 |
| BR9711721A (en) | 1999-08-24 |
| NO991123D0 (en) | 1999-03-08 |
| EP0929555A1 (en) | 1999-07-21 |
| CO4900069A1 (en) | 2000-03-27 |
| JP2001500494A (en) | 2001-01-16 |
| CZ51999A3 (en) | 1999-05-12 |
| PE98998A1 (en) | 1998-12-24 |
| AU4094597A (en) | 1998-03-26 |
| SK27499A3 (en) | 2000-02-14 |
| PL332044A1 (en) | 1999-08-16 |
| HUP0000264A2 (en) | 2000-06-28 |
| TR199900496T2 (en) | 1999-06-21 |
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